Depression is one of the leading causes of disability worldwide, with many patients inadequately treated, and at its worst results in suicide. Thus, new therapeutic strategies are critically needed. Such strategies require a holistic understanding of the precise neuronal subtypes and molecular mechanisms underlying depression. Imaging and genetic studies have identified key neurobiological markers in depressed patients. However, information relating maladaptive neuronal populations in depression with the genetics of depression is lacking. We can overcome this limitation by employing a multidisciplinary approach to investigate a novel risk gene for major depressive disorder (MDD), the neuronal amino acid transporter Slc6a15, and endogenous opioid signaling in a nucleus accumbens microcircuit, which is known to mediate negative emotional states. Our studies employ a multidisciplinary approach including cell subtype and circuit selective molecular profiling, cell subtype genetic targeting, and optogenetics to uncover novel molecular mechanisms in this nucleus accumbens microcircuit in depression. We have the ability to profile Slc6a15 levels in selective neuron populations in preclinical models of depression. In parallel we have developed novel genetic tools to manipulate Slc6a15 levels in selective neuronal populations and assess the impact of Slc6a15 levels in depression related behaviors in rodents. Using these tools we will assess the effects of Slc6a15 on endogenous opioid signaling and study how altering endogenous opioid signaling, within this nucleus accumbens microcircuit, impacts depression related behaviors. Findings from these proposed studies could uncover multiple avenues of therapeutic targeting that can greatly impact the lives of individuals suffering from this chronic disease.